pediatrics 1981 gunn 61 7

1981;67;61PediatricsTania Gunn, Elena R. Reece, Katherine Metrakos and Eleanor Colle

Depressed T Cells Following Neonatal Steroid Treatment

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PEDIATRICS Vol. 67 No. 1 January 1981 61

Depressed T Cells Following Neonatal SteroidTreatment

Tania Gunn, MD, Elena R. Reece, MD, Katherine Metrakos, MD, and

Eleanor Colle, MD

From the Departments of Neonatology, Clinical Immunology, Electroencephalographyand Endocrinology, McGill University, and Montreal Children ‘s Hospital ResearchInstitute, Montreal

ABSTRACT. Forty-four patients received two doses of12.5 mg/kg of hydrocortisone or placebo on the first dayof life in attempted therapy for respiratory distress syn-

drome. Follow-up studies were performed on survivors at5 years of age in ten steroid-treated and seven placebo-treated respiratory distress syndrome subjects. Therewere no significant differences in growth, inteffigence

tests, or neurologic examinations in the patients assessed.Abnormal EEGs are present in both groups. Immunologictests showed no differences in lymphocyte counts, im-munoglobulin levels, diphtheria and tetanus antibody

titers, or complement components. Diminished percent-ages of T lymphocytes were found in steroid patients(53%) compared to control subjects (69%). There were

also increased percentages of lymphocytes with C3 recep-

tors in steroid patients (20.1%) compared to control pa-tients (13.8%). Episodes of otitis and/or pneumonia were

documented in eight of 1 1 steroid-treated patients be-tween the ages of 1 and 5 years, compared to two of sevenpatients in the placebo group in the same time period. Itis concluded that large doses of steroids on the first dayof life may induce lasting immunologic abnormalities andmay predispose to an increased incidence of infections.Pediatrics 67:61-67, 1981; corticosteroids, T cells, respi-ratory distress syndrome, neonates.

The short history of neonatal medicine is replete

with therapeutic misadventures. Any new pharma-

cologic regimen must be carefully evaluated for

both unexpected side effects and long-term seque-lae.

Received for publication Sep 26, 1978; accepted July 6, 1980.Read in part at the 48th Annual Meeting of the Society forPediatric Research, New York, April 26-28, 1978.Reprint requests to (ERR.) Department of Clinical Immunol-ogy, Montreal Children’s Hospital, Montreal, Quebec H3H 1P3.

Dr Gunn’s present address: St Helen’s Hospital, Auckland, NewZealand.PEDIATRICS (ISSN 0031 4005). Copyright © 1981 by theAmerican Academy of Pediatrics.

The efficacy of glucocorticoid treatment in accel-

erating the rate of lung development in late fetal

life has been shown by numerous animalt3 and

human studies.4 Potential toxicity for the fetus and

newborn infant may be inferred from the late effects

of neonatally administered corticoids found in ani-

mal studies. These studies have been reviewed re-

cently,5 and effects include impaired central ner-

vous system development71’ diminished placental

growth,’2 thymolymphatic cellular depletion,7t�6

lasting impairment of immunologic responsive-

ness,8”6”7 runting similar to that seen in neonatal

thymectomy,’3’�2#{176} and decreased life span with in-

creased infections.’8

In 1971 a controlled trial using postnatal hydro-

cortisone in pharmacologic doses for infants with

the respiratory distress syndrome was carried out

in the neonatal intensive care unit of the Montreal

Children’s Hospital and showed no benefit to the

steroid-treated infants.2’ Blood levels of cortico-

steroids which exceeded 500 mg/100 ml in a few

infants were found in the steroid-treated group.

Pathologic findings from the infants who died in

the neonatal period showed a significant association

between intraventncular hemorrhage and steroid

treatment.22

Follow-up studies of the infants who survived for

the first year of life showed a trend toward an

increased incidence of neurologic and encephalo-

graphic abnormalities and a significant difference

in motor development in the steroid-treated infants

at 1 year of age.23

This paper presents continued follow-up investi-

gation of the children from the same study.

PATIENTS AND METHODS

Of the original 44 patients admitted to the study,

22 received 12.5 mg/kg of hydrocortisone in two

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62 DEPRESSED T CELLS FOLLOWING NEONATAL STEROID TREATMENT

doses 12 hours apart in the first day of life and 22

received placebo. The neonatal courses of the two

groups were similar. Fourteen infants in each group

survived the neonatal period and 12 infants in each

group were available for study at 1 year of age.

These children have been followed at yearly in-

tervals in the neonatal follow-up clinic with records

of interim infections, measurements of height,

weight, and head circumference, and neurologic and

developmental examinations.

At 4 years of age 12 children from the steroid

group and ten of the placebo group were still fol-

lowed in the clinic. Of the 12 surviving placebo-

treated children who were evaluated at 1 year of

age, ten were studied completely for four years but

only seven were still available for study at 5 years

of age. At this time weight index and height index

were calculated for each child from the expected

date of delivery and the formula: weight (height)

index = weight (height)/age24 with percentiles from

the Stuart grid25 and age from estimated date of

conception. The head circumferences were plotted

on the Nelihaus grid.26

The children were retested with psychometric

evaluations using the Wechsler Preschool and Pri-

mary Scale of Intelligence (WPPSI),27 and Bender-

Gestalt, scored according to Koppitz,� or Rutger’s

A Drawing Age?� Electroencephalograms were re-

peated and were interpreted without knowledge of

steroid treatment status. Each abnormal tracing

was classified according to severity and the abnor-

mality described as, focal, paroxysmal, asymmetri-

cal, or epileptiform.

Immune competence was reassessed at 5 years of

age. Total lymphocyte counts were estimated from

the peripheral white blood cell and differential

counts. Levels of the complement components C3

and C4 were determined by radial immunodiffusion

using commercial plates. Ci-esterase inhibitor and

Clq levels were estimated by Ouchterlony double

diffusion. Assessments of B-cell function included

protein electrophoresis, determinations of IgG, IgA,

1gM, and IgD using commercial plates and IgE by

paper radioimmunosorbent test (PRIST, Pharma-

cia). Antibodies to tetanus and diphtheria were

measured by hemagglutination. Cell-mediated im-

munity was assessed by intradermal delayed skin

tests using dermatophytin, purified protein denva-

tive, Candida, streptokinase, and streptodornase

(Varidase), and histoplasmin or tetanus toxoid. T-

and B-cell quantitation was performed utilizing

mononuclear cells separated from heparimzed

whole blood by Ficoll-Hypaque density gradient

centrifugation.3#{176} The cell suspension was washed in

medium 199 and incubated with latex particles for

one hour at 37 C.3’ Monocytes ingesting latex were

not counted when lymphocyte subpopulations were

quantitated. This incubation also allowed labile

membrane immunoglobulin to elute from cells with

Fc receptors.32 T lymphocytes (E-RFC) were iden-

tified by the formation of rosettes with sheep red

cells.33 Receptors for the third component of com-

plement (C3) were detected by the adherence of

fluoresceinated Salmonella typhi, sensitized with

human complement, to lymphocytes.� Fc receptors

were determined by rosette formation of lympho-

cytes with human type 0 Rh+ red cells sensitized

with Ripley anti-CD antiserum.� Surface mem-

brane immunoglubulin (SmIG) was detected with

fluoresceinated antisera, both polyvalent and spe-

cific for individual heavy and light chains.36 All

studies were performed without knowledge of the

patients’ treatment status.

RESULTS

Of the 12 surviving children who had received

hydrocortisone and were evaluated at 1 year of age,

1 1 were studied completely for five years. Reports,

including neurologic evaluation were obtained from

another hospital for one other boy who is retarded,

hyperactive, and mute with moderate spastic diple-

gia. This boy probably had an intracranial hemor-

rhage in the neonatal period. The 1 1 other steroid-

treated and seven placebo-treated children studied

at 5 to 6 years of age had normal neurologic exam-

inations.

Mean weight and height indices and head circum-

ferences are shown in Table 1. All measurements

for both groups are between the 25th and 50th

percentiles and are not significantly different. The

mean heights and weights of the parents (fathers:

173 ± 8 cm, 77 ± 10 kg; mothers:160 ± 7 cm, 52 ±

7 kg) were similar to the Canadian average.37

Table 2 shows the results of psychometric testing.

The mean IQ was 100.7 ± 10.8 in the steroid group

and 108 ± 1 1.3 in the control group; these scores

are not significantly different nor are the mean

verbal or performance scores from the WPPSI. The

mean Rutger or Bender-Gestalt scores also show no

significant differences between the two groups. The

socioeconomic level was similar in the two groups.23

Not all of the children had started school yet. One

child in the placebo group has a history of poor

writing and poor fine motor coordination in school.

One child in the steroid group has both emotional

and learning problems, but two of his older brothers

also have severe learning problems.

EEG abnormalities are seen in both groups and

are shown in Table 3. One child in the steroid group

who has an active epileptogenic disturbance has

had no seizures. One child in the placebo group,

whose parents refused an EEG, has had a febrile

convulsion.




TABLE 1 . Growth at 1 and 4 Years of Age in Steroid-Treated and Control Patients*

ARTICLES 63

-- Patients Weight Index Height Index Head Circumference

1 year of age

Steroid-treated (12)t 0.93 ± 0.27 0.97 ± 0.18 47.2 ± 1.0Control (12) 0.98 ± 0.4 0.99 ± 0.18 46.6 ± 1.5

4 years of ageSteroid-treated (12) 0.91 ± 0.23 0.90 ± 0.15 51.5 ± 1.1Control (10) 0.97 ± 0.25 0.93 ± 0.14 51.3 ± 1.7

* Values are mean number (±1 SD).

t Number of children in each group is shown in parentheses.

TABLE 2. Psychometric Testing�WPPSI* in Steroid-Treated and Control Patients

Patients Full IQ Scores Verbal Performance Perceptual

Steroid-treated (10) 107.1 ± 10.8 101 104 2.5 moControl (7) 108.2 ± 11.3 105 109 4.0 mo

S Wechsler Preschool and Primary Scale of Intelligence.

TABLE 3. Electroencephalograms in Steroid-Treated and Control Patients

. - - RefusedPatients Epileptogen,c Paroxysmal Irregular Test Normal

Steroid-treated (10) 2 0 1 1 6

Control (7) 0 1 3 2* 1

* One febrile convulsion.

IMMUNOLOGIC DATA

The results of immunologic testing are shown in

Table 4 and the Figure. There were no significant

differences in total lymphocyte counts, levels of

immunoglobulins, diphtheria and tetanus titers, or

complement components in the two groups. All

children had at least one positive delayed skin test.

Patients who had received steroids had a signifi-

cantly lower percentage of E-RFC than the control

group: 53% and 69%, respectively (P < .0005). In

some patients decreased E-RFC percentages were

associated with higher percentages of cells with C3

receptors (20. 1%) than observed in the adult or

control groups (10.4% and 13.8%, respectively, P <

.025) . No significant differences were observed in

percentages of cells with surface immunoglobulins

or Fc receptors.The number of infections between 1 and 5 years

of age was greater in the steroid group with eight of

11 patients having otitis and/or x-ray proven pneu-

monia compared to only two of seven patients in

the control group having otitis (Table 5). One child

in each group has had asthmatic attacks.

DISCUSSION

Although this follow-up study was designed to

address the major categories of long-term sequelae

reported in animals given neonatal steroids, it was

surprising to the authors to find diminished per-

centages of E-RFC at 5 years of age in children who

had received steroids on the first day of life. Man,

along with monkeys and guinea pigs, has been con-

sidered relatively resistant to steroid effects on the

immune system. Claman et al� evaluated steroid-

induced thymocyte lysis in humans, mice, and

guinea pigs and found human thymocytes relatively

resistant to this treatment. However, the thymo-

cytes of the youngest subject studied (age 11

months) demonstrated greater susceptibility to lysis

than thymocytes of older subjects. Reduction in

thymic size with oral steroid administration has

also been demonstrated radiologically in human

neonates.39 Evaluation of cardiothymic/thoracic ra-

tios immediately after birth in these infants and in

those who received prenatal steroids 40,41 revealed

a slightly more rapid decline in cardiothymic/tho-

racic ratios in postnatally steroid-treated infants

compared to those given placebo, while in prena-

tally treated infants the cardiothymic/thoracic ra-

tio was greater in patients who developed respira-

tory distress syndrome, but no effect of steroids was

found.Human and animal studies have shown diverse

effects of glucocorticoids on blood leukocyte kinet-

ics and function. T-lymphocyte numbers and func-

tion are more susceptible to their effects than are B

lymphocytes, although many of the effects on cell-

mediated immune functions are secondary to the

relative steroid sensitivity of the monocyte-macro-

phage system.42 It is thought that T cells develop

resistance to functional effects of steroids, in part




because of maturational changes in the thymus43’ �

� and the differentiating effects ofthymic hormones,45

� 0 � and in part because of further differentiation after

E! � � exposure to antigen.46 In mature mice, thymectomyii or cortisone administration leads to no detectable

long-term effects.47 Conversely, low concentrations

.5 � � of steroids in vitro have been shown to enhance

� � � 0 � thymocyte differentiation rather than to cause cy-:�. : .� � ,:� totoxicity,48 and glucocorticoid antagonists interfere� � 0 with the normal ontogeny of cell-mediated immune

function.49

�c � The long-term implications of the immunologic

� :g � � findings in these patients are not readily apparentC,, �; � C\t as various disorders are associated with diminished

numbers of T cells, including immunodeficiency

states, autoimmune disorders, malignancies, and

� Lt� Lt� acute infections. A null population is suggested by� � �;; � �; � the failure to identify large percentages of the cells

-� - � - � from several steroid-treated children by the tech-

niques utilized. That the association of diminished

E-RFC and elevated numbers of cells with comple-

� �. � � � ment receptors may indicate an early T cell popu-� � � ,:� ;� lation is supported by a recent report that comple-

ment receptors may be a marker of early T cells in

�. � man.�#{176}Additionally young mice injected with cor-.2� � � � � tisone demonstrate a relative enrichment of C3L) � - 2� receptor-bearing thymocytes.5’

� The increased incidence of bronchopneumonia

.� � and otitis media in the children who received hy-

� � c� � � � drocortisone was, again, unexpected. Elucidation of-� - � ? � g � whether this was a chance occurence, as the num-

� bers of children in each group are small and the

� - incidence of childhood infections is widely variable,

-� � � � � or secondary to the therapy depends on further.� .� � � :� � � careful follow-up of these children and others who

� ,� V V receive steroids at an early age.

� There were no differences in height, weight, or� .� � � head circumference at 1 year or 4 years of age

.� � � � c�1 � �i between corticosteroid-treated children and the

� � � � control group. There were also no significant differ-

.� ences in the results of psychometric testing or in

�c � the general behavior of the children at 5 years of

� � � � � �2 � age. School performance wifi be evaluated as theE� � � � S� “ � children progress through school..�c � The differences in motor skills found at 1 year by

-� = Fitzhardinge et al23 in the steroid-treated group

� c� � � � were not apparent at 5 years of age. The results of

� .� � � � the mean performance and verbal scores were not

: � � significantly different in the two groups. No differ-� ences were apparent in testing for perceptual prob-

-� lems but the children are stifi too young for this to

� � be fully assessed. The EEG results showed an in-

.� ! crease in severe abnormalities in the steroid-treated“2W � � group, but one child in the control group had a

� :� 7 � � � � febrile convulsion, and an EEG was refused. There� � I>< � � I>< � were abnormal EEGs found in four of 12 steroid-I- &� L) treated children at 1 year of age. There are no





E-RFC Fc C3 Sm IG

100 35

I � N.onatal steroid tr.at.d

90 30 � � 0 N.onatal controls

. 0 A � #{149}Adult controls-� 80

25E

�C;; 70 20 -

a #{149} 0� T oo#{224}

: 08� #{149} A� 60 A 15 #{149} I

.� � A #{149} I A0

�L - #{149}1 �0A: so A I AA . -

10 _00 � AA � 0AA0

. I 0 #{149}. 0 A&- A #{149}#{176}AA #{149} . 0 A

I 00 AA � � . A

I40 A

A o

I30 0 oA

p’0.0005 p< 0.025

Figure. Lymphocyte surface markers. Percentage of lymphocytes expressing Fc and C3receptors and bearing surface-membrane immunoglobulins represented on the same scale.

ARTICLES 65

TABLE 5. Infections Between the Ages of 1 and 5 Years in Steroid-Treated and ControlPatients

Steroid-tre

Control (7)

Patients

ated (11)

Pneumonia

3. . .

Otitis Media

62

Upper RespiratoryInfections Only

3

5

clinical effects correlated with these changes at this

time.

The children receiving steroids were all prema-

turely born. The mean plasma levels of cortisol

resulting were greater than 100 mg/100 ml for 48

hours following injection as compared with values

of 30 mg/100 ml for the stressed placebo-treated

infants. The most frequently used steroid prepara-

tions in the treatment of the fetus and newborn, at

this time, are dexamethasone and betamethasone

administered to the mother, often on a schedule

which requires weekly repetition of the dose. Data

on peak levels of the steroids measured following

birth of the infant52’� are difficult to compare with

those found in this study because of differences in

plasma protein and tissue binding, duration of ac-

tion, and variable estimates of comparable poten-

cies of various steroid analogues.

RELEVANCE

The finding of diminished T cells at 5 years of

age in children who received steroids on the first

day of life emphasizes the importance of ongoing

follow-up investigations to assess the long-term ef-

fects of steroids in infants who receive them at an

early age or prenatally. Since corticosteroid effects

in developing organisms vary depending on the age

of administration and dose administered, careful

stratification of study populations by gestational

age and steroid dosage should be a cardinal feature

of such studies.

SUMMARY

At 5 years of age ten children who received hy-

drocortisone on the first day of life in attempted

therapy of respiratory distress syndrome and seven

placebo-treated infants were assessed for growth,

psychometric testing, neurologic status, electroen-

cephalograms, immunologic status, and incidence

of infections. Diminished percentages of T cells

were found in children who had received steroids,

associated in some with increased percentages of

cells with complement receptors. There was also an

increased number of infections in steroid-treated

children. It is concluded that even brief therapy

with corticosteroids in infants may result in lasting

immunologic impairment.





ACKNOWLEDGMENT

This work was supported by the Nathan Steinberg

Family Foundation.

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THE SAD FATE OF DR MICHAEL UNDERWOOD’S WIDOWED DAUGHTER

The most advanced writer on diseases of children in the 18th century,

according to G. F. Still, was Michael Underwood.’ He was the first to describe

sclerema neonatorum, apneic attacks in the newborn, “malignant familial jaun-

dice” of the newborn, and the first to write about congenital heart disease of

children. His Treatise on the Diseases of Children (1784) passed through at

least 17 editions and remained in favor for more than 60 years; the last American

edition appeared in 1842.

Unfortunately, Underwood apparently received no royalties from his textbook

and died without being able to provide for his widowed daughter. Friends tried

to help her by putting together a book entitled Extracts from the Diary of the

Late Michael Underwood, M.D. (1823) that would then be sold to subscribers.

In the prospectus for this book Underwood’s friends poignantly described

their reasons for publishing this book as follows:

It is confidently hoped that the Friends of the late Dr Underwood, and more especiallythose in the Profession who are acquainted with the estimable works which he publishedon the “Diseases and Disorders of Children” &c. wifi feel an interest in the case of hiswidowed Daughter, who now stands in need of the benevolent exertions of her Friends.She is in her fiftieth year, and is borne down by an accumulation of troubles, arising

partly from the loss of relatives and friends, and partly from serious mental debility,which frequently incapacitates her for the humble and precarious employment ofneedlework, in which she is at other times engaged. Thus reduced, she has at lengthconsented to make an appeal to the liberality of her Friends and humbly to solicit theirkind support of the Publication now projected, which she hopes will enable her to raisea small sum to provide her with a few comforts in the decline of life. The situation of theapplicant is the more painful to her feelings from the recollection of those enjoyments,and even indulgences, which in the plenitude of her father’s fame, she had the happinessto experience.2

As far as I can determine, approximately 500 copies of the book were sold to

subscribers. I doubt whether the profit made from this sale was large enough to

really benefit Dr Underwood’s daughter.

Noted by T.E.C., Jr, MD

REFERENCES

1. Still GF: The History ofPaediatrics. London, Oxford University Press, 1931, pp 476-477.2. Extracts from the Diary of the Late Michael Underwood, M.D. London, Hatchard and Son,

1823.




1981;67;61PediatricsTania Gunn, Elena R. Reece, Katherine Metrakos and Eleanor Colle

Depressed T Cells Following Neonatal Steroid Treatment

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